Control of cardiovascular responses to stress by endocannabinoid neurotransmission in the bed nucleus of the stria terminalis in rats: interaction with the NMDA receptor/NO/cGMP/protein kinase g signaling pathway and involvement of lateral hypothalamus

• Grant number: 16/05028-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2016
• End date: June 30, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Carlos Cesar Crestani
• Grantee: Lucas Gomes de Souza
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 19/25654-0 - Effect of pharmacological treatment with fatty acid amino hydrolase inhibitor on behavioral responses to chronic unpredictable stress: evaluation of the involvement of morphological changes in the bed nucleus of the stria terminalis, BE.EP.DR

Abstract

Physiological responses, including autonomic and neuroendocrine changes, are evoked during threat aversive to maintenance of homeostasis. Although the relevance, the neurobiological mechanisms involved in etiology and control of these responses are poorly understood. The bed nucleus of the stria terminal (BNST) is a limbic structures localized in the rostral prosencephalon involved in autonomic, neuroendocrine and behavioral responses to stress. A recent study from our group demonstrated an inhibitory influence of the endocannabinoid signaling in the BNST, acting via local CB1 receptor, in tachycardiac response to acute restraint stress, without affecting the blood pressure increase and cutaneous vasoconstriction responses. It has been reported an inhibitory action of BNST CB1 receptor in local glutamatergic neurotransmission. An important mechanism of nitric oxide (NO) formation in the central nervous system is mediated by activation of the NMDA glutamatergic receptor, which in turn activates the neuronal isoform of the NO synthases enzyme (nNOS). The NO has several signaling mechanisms, but the main is mediated by stimulation of cyclic guanosine monophosphate (cGMP) formation that in turn activates protein kinase G. Although above evidence, a possible involvement of local glutamatergic and nitrergic signaling in regulation of cardiovascular function by BNST endocannabinoid neurotransmission has never been investigated. Therefore, a first hypothesis to be tested in the present study is that the control of cardiovascular responses during an acute stress session by BNST CB1 receptor is mediated by local glutamatergic neurotransmission, acting via NMDA receptors and dependent of NO formation and activation of the soluble guanylate ciclase and protein kinase G. The neural circuitry involved in control of cardiovascular responses to stress by the BNST is poorly understood. However, it was identified projections, possible GABAergic, from the BNST to the lateral hypothalamus (LH). A recent study demonstrated an inhibitory influence of the LH in tachycardiac response to acute restraint stress. Thus, considering that control of cardiovascular responses to stress by BNST endocannabinoid signaling is mediated by a modulation of local glutamatergic neurotransmission, a second hypothesis to be tested in the present study is that the endocannabinoid formation within the BNST during stress decrease the local glutamate release, which in turn reduces the activation of local GABAergic neurons that project to LH, causing a lesser inhibition of neurons in the LH. This effect would mediate the inhibitory influence of BSNT endocannabinoid signaling in tachycardiac response to stress. Therefore, the aims of the present study are: 1) to investigate the involvement of the NMDA receptor/NO/cGMP/protein kinase G signaling pathway in control of cardiovascular responses to acute restraint stress by the CB1 receptor within the BNST; 2) to characterize the role of GABAergic neurotransmission in the LH in control of cardiovascular responses to acute restraint stress in rats; and 3) to evaluate the involvement of LH GABAergic neurotransmission in control of cardiovascular responses to acute restraint stress by the CB1 receptor in the BNST. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES-DE-SOUZA, LUCAS; COSTA-FERREIRA, WILLIAN; MENDONCA, MICHELLE M.; XAVIER, CARLOS H.; CRESTANI, CARLOS C.. Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats. SCIENTIFIC REPORTS, v. 11, n. 1, AUG 9 2021. (16/05028-9, 16/05218-2, 19/24478-3, 17/19249-0)

GOMES-DE-SOUZA, LUCAS; BENINI, RICARDO; COSTA-FERREIRA, WILLIAN; CRESTANI, CARLOS C.. GAB(A) but not GABA(B) receptors in the lateral hypothalamus modulate the tachycardic response to emotional stress in rats. European Neuropsychopharmacology, v. 29, n. 5, p. 672-680, MAY 2019. (15/05922-9, 16/05218-2, 16/05028-9, 17/19249-0)

GOMES-DE-SOUZA, LUCAS; BIANCHI, PAULA C.; COSTA-FERREIRA, WILLIAN; TOMEO, RODRIGO A.; CRUZ, FABIO C.; CRESTANI, CARLOS C.. CB1 and CB2 receptors in the bed nucleus of the stria terminalis differently modulate anxiety-like behaviors in rats. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 110, AUG 30 2021. (16/05028-9, 16/05218-2)

GOMES-DE-SOUZA, L.; OLIVEIRA, L. A.; BENINI, R.; COSTA-FERREIRA, W.; CRESTANI, C. C.. Endocannabinoid neurotransmission inhibits the formation of nitric oxide in the bed nucleus stria terminalis during acute restraint stress in rats. European Neuropsychopharmacology, v. 27, p. 2-pg., 2017-10-01. (16/05028-9)